Intheinheritedhomozygousconditionknownassickle cell disease, affectedindividualshaveanaminoacidsubstitution(valineforglutamicacid)ontheβ chainoftheHgbmolecule.ThiscreatesasicklecellHgb(HgbS),which,whennotboundtooxygen(deoxyhemoglobinordesaturatedHgb),cantransformintoastiffgelatinousmaterialthatdistortsthenormalbiconcaveshapeoftheredbloodcelltoacrescent,orsickle-shaped,form.Thischangeinappearancefromsphericaltoasickleshapeincreasesthetendencyoftheredbloodcelltoformthrombiorclotsthatobstructsmallvesselsandcreatesaclinicalconditionknownasacute sickle cell episode. Thesymptomsofsuchanepisodevary,dependingonthesiteoftheobstruction(e.g.,inthebrain,stroke;inthelungs,pulmonaryinfarction)andarecommonlyassociatedwithintensepain.Thespleenisacommonsiteofobstruction/infarction,andtheensuingtissuedamagecompromisestheimmunecapabilitiesofaffectedindividualsandrendersthemsusceptibletorecurrentinfections.Inthehomozygousform,thisconditionislife-shortening;however,individualswiththeheterozygousformareresistanttomalaria.Thusanindividualwithheterozygousalleleshasasurvivaladvantageinregionsoftheworldwheremalariaisprevalent,whichmayexplainwhythesicklecellmutationhasbeenpreservedthroughevolution.TheincreasedaffinityofHgbFforO2confersadvantagestoindividualswithsicklecelldiseaseinthatthecellsdonotdesaturateasmuchwhenO2isreleasedfromHgbtothetissueandthusarelesslikelytobecomedeformedinthesickleshape.SicklecelldiseaseismostprevalentamongindividualsofAfricanAmericandescent,butitisalsoobservedinHispanic,Turkish,Asian,andotherethnicgroups.
Hgb for O2 decreases, which enhances O2 dissociation. This results in decreased Hgb binding to O2 at a given PO2, which causes the P50 to increase. When the affinity of Hgb for O2 increases, the curve is shifted to the left, which causes the P50 to decrease. In this state, O2 dissociation and delivery to tissue are inhibited. Shifts to the right or left of the dissociation curve have little effect when they occur at O2 partial pressures within the normal range (80 to 100 mm Hg). However, at O2 partial pressures below 60 mm Hg (steep part of the curve), shifts in the oxyhemoglobin dissociation curve can dramatically influence O2 transport.